antioxidants Review Polyphenols from Food and Natural Products: Neuroprotection and Safety Rui F. M. Silva 1 and Lea Pogaˇcnik 2,* 1 Research Institute for Medicines (iMed.ULisboa) and Department of Biochemistry and Human Biology (DBBH), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal; rfmsilva@ff.ulisboa.pt 2 Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia * Correspondence: [email protected] Received: 6 December 2019; Accepted: 7 January 2020; Published: 10 January 2020 Abstract: Polyphenols are naturally occurring micronutrients that are present in many food sources. Besides being potent antioxidants, these molecules may also possess anti-inflammatory properties. Many studies have highlighted their potential role in the prevention and treatment of various pathological conditions connected to oxidative stress and inflammation (e.g., cancer, and cardiovascular and neurodegenerative disorders). Neurodegenerative diseases are globally one of the main causes of death and represent an enormous burden in terms of human suffering, social distress, and economic costs. Recent data expanded on the initial antioxidant-based mechanism of polyphenols’ action by showing that they are also able to modulate several cell-signaling pathways and mediators. The proposed benefits of polyphenols, either as protective/prophylactic substances or as therapeutic molecules, may be achieved by the consumption of a natural polyphenol-enriched diet, by their use as food supplements, or with formulations as pharmaceutical drugs/nutraceuticals. It has also been proved that the health effects of polyphenols depend on the consumed amount and their bioavailability. However, their overconsumption may raise safety concerns due to the accumulation of high levels of these molecules in the organism, particularly if we consider the loose regulatory legislation regarding the commercialization and use of food supplements. This review addresses the main beneficial effects of food polyphenols, and focuses on neuroprotection and the safety issues related to overconsumption. Keywords: bioavailability; in vitro models; neuroprotection; neurotoxicity; polyphenols; toxicity 1. Introduction Polyphenols are naturally occurring micronutrients that are present in plants as essential physiological compounds [1]. They comprise a wide family of molecules bearing one or more phenolic rings and are present in many food sources like wine, green tea, grapes, vegetables, red fruits, and coffee [2,3]. It is generally accepted that most polyphenols are potent antioxidants [4,5] and may also possess anti-inflammatory properties [6,7]. Those properties attracted the interest of researchers to polyphenols, and many studies highlighted their potential role in the prevention and treatment of various pathological conditions connected to oxidative stress and inflammation, like cancer and cardiovascular and neurodegenerative disorders, and also of pollutant-induced cell damage [8–12]. Moreover, those food products are relatively abundant in the human diet, and several foods and beverages can provide more than 1 mg of polyphenolic content per serving, as shown by the study of Pérez–Jiménez et al. (2010) based on data from the Phenol-Explorer database [13]. As an example, by using the same database, Godos et al. (2017) estimated that an Italian Antioxidants 2020, 9, 61; doi:10.3390/antiox9010061 www.mdpi.com/journal/antioxidants Antioxidants 2020, 9, 61 2 of 13 study population had a mean intake of approximately 660 mg of polyphenols per day, obtained from nuts, tea, coffee, cherries, citrus fruits, vegetables, chocolate, and red wine [14], all regular constituents of the Mediterranean diet [15], included in the list of the Intangible Cultural Heritage of Humanity by UNESCO. In fact, olive-oil components were described as relevant pharmacological molecules [16]. However, major dietary sources of polyphenols may vary depending on the traditional diets adopted in various countries, thus, in Northern and Eastern European countries, the main dietary sources of polyphenols are represented mostly by beverages, such as coffee and tea [17,18], while in Southern European and Mediterranean countries, important dietary sources may be nuts, olive oil, fruits, and vegetables [14,19]. Recently, the food industry also became interested in byproducts derived from plants and fruits due to their rich content of polyphenols, and potential use in functional foods or food supplements [20]. Although some phenolic compounds are specific to some fruits and plants, many polyphenols are present in several food sources [2], and many fruits and vegetables produce more than one particular type of phenol, being more or less rich in an assortment of those compounds [21]. Furthermore, the level of polyphenols in the same plant is not constant, but varies with, for example, crop and atmospheric conditions [20,21]. This variation of polyphenol content in what appears to be the same plant or fruit makes it difficult to assess the ingested amount by a particular person. All these facts have to be considered in the balance of the potential beneficial roles of polyphenols versus the possibility of intensified accumulation, safe consumption, and toxic effects. Novel data expanded on the initial antioxidant-based mechanism of polyphenols’ action by showing that they are also able to modulate several cell-signaling pathways and mediators in a wide range of human pathologies. In a recent publication, Patel et al. (2019) revised the pharmacological applications of curcumin in several diseases [22], as well as a wide range of pleiotropic actions in the modulation of cell-signal molecules. In diabetes, tea polyphenols were able to reduce the senescence of glomerular mesangial cells by regulating the activity of miR-126/Akt-p53-p21 pathways [23]. The consumption of flavonoid compounds seemed to also have a beneficial effect on colon-cancer prevention by modulating lysosome enzymes, increasing the expression of apoptotic factors like Bax, Bcl2, and caspase-3 in cancer cells, and regulating cellular respiratory and mitochondrial enzymes [11]. A recent review also pointed out the beneficial role of dietary polyphenols quercetin and epigallocatechin gallate (EGCG) in the prevention and treatment of obesity, with important impact on the prevention of cardiovascular diseases. Quercetin appeared to modulate adipogenic pathways like the adenosine-50-monophosphate (AMP)-activated protein kinase, and upregulate the levels of phosphorylated AMP-activated protein kinase (AMPK) and its substrate, acetyl-CoA carboxylase, in 3T3-L1 preadipocytes, while EGCG appeared to inhibit the proliferation and differentiation of 3T3-L1 preadipocytes in mature adipocytes by arresting the cell cycle [24]. However, it is still controversial whether or not these products can naturally increase intrinsic brain defenses and avoid, or at least reduce, the initial insults that lead to the neurodegenerative process. 2. Beneficial Effects of Polyphenols and Neuroprotection Neurodegenerative diseases are typically characterized as pathological conditions where particular groups of neurons are damaged or lost, disturbing the normal function of the central nervous system, either by impairing cognitive functions, motor functions, or both. Many of those illnesses are commonly associated with aging, but it is currently known that neurodegeneration develops in a subclinical form over years, with neuronal death occurring progressively over a lifetime, much before the first clinical signs are noticeable. Current predictors indicate a continuous increase in dementia cases that, between 2005 and 2030, may reach about 50% of the aged population [25]. Numerous studies [26–29] have been dedicated to the cellular mechanisms for neurodegeneration in several pathological conditions, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, as well as amyotrophic lateral sclerosis. However, there are currently no effective therapies available to treat such diseases besides symptom amelioration [30,31]. Antioxidants 2020, 9, 61 3 of 13 In spite of their specific pathways, many of those conditions share common mechanisms, such as neuroinflammation [32] and oxidative stress [29,33]. In fact, the possible role of reduced expression or imbalance of oxidative-stress regulatory genes in aging and neurodegeneration, as well as the possible protection by antioxidants, was already reviewed [34]. Therefore, any strategies that can delay or prevent the onset of the disease, conveying neuroprotection, may be as important as the ones designed to treat it. The notion that diet can have a crucial role as one of those strategies has recently been proposed, leading to several studies focused on the importance of nutritional consumption of natural products, as food itself or as food supplements, that may convey neuroprotection [35,36]. One of the first indications of biological activity from food-derived molecules was the discovery of the antibacterial properties of curcumin, published in Nature in the late 1940s by Schraufstatter and Bernt [37]. Other food polyphenols, particularly resveratrol, also attracted the attention of researchers, as suggested by the possible association between red-wine consumption in France and the low incidences of coronary heart disease [38]. This association could be explained by the antioxidative properties of food polyphenols, in this case resveratrol, that were also found to convey neuroprotective activity